Breathing New Life Into Diseased Lungs: a Promising Journey to Treat Pulmonary Fibrosis

“I need some breathing space”. Often, we use this phrase when we need rest. However, those words could mean something more for a person terminally ill with pulmonary fibrosis (PF), a lung disease that makes the patient routinely gasp for his or her breath. It involves long-term scarring of the lung tissues, which affects individuals mostly in their golden years and untreated patients survive for 3 to 5 years after diagnosis.¹

In general, PF is hard to determine as it can arise frequently due to unknown reasons and sometimes as a result of occupational exposures, drug toxicity, viral infections, and genetic susceptibility. Further, the characteristics of PF overlap with other respiratory ailments, including lung cancer, thereby making its diagnosis more challenging.

Interestingly, some researchers have suggested that patients with chronic lung fibrosis could be predisposed to develop lung cancer.² Although PF is thought to be a rare disease, according to the American Lung Association, nearly 58,000 new cases are diagnosed each year in the United States alone, indicating that it is no longer an uncommon lung disorder.

The recent rise in the number of PF cases has been compounded by long-lasting consequences of post-coronavirus 2019 (COVID-19) infections.³ Lack of awareness is leading to unnoticed occurrences of PF and there have been a number of cases of wrong diagnosis due to the absence of any definite biomarkers (biomolecules in our body that signifies either normalcy or the presence of an abnormality).

The present treatment involves alleviation of symptoms and slowing down the disease's progression without any reversal of the lung damage, proving it to be a limited therapeutic strategy. Hence, current research focuses on understanding the molecular mechanisms with the hope of identifying new drug targets in cells and finding effective therapies to reverse the diseased state, and also on strategies to improve the management of PF.

How Does Fibrosis Develop in Human Lungs?

In the early days, it was believed that chronic inflammation (a kind of response by the immune system) contributed to the development of disease in the lungs. However, recent studies indicate that a complicated interplay of genetic and environmental factors causes frequent micro-injuries to the ageing epithelial cells, which line the alveoli (tiny air sacs in the lung).

These cellular insults contribute to the changes in the behaviour and communication of both epithelial cells and fibroblasts (cells that synthesise and maintain connective tissues) in the lung. Fibroblasts deposit excess extracellular collagen during alveolar injury repair and scar the functional area within the lungs.

Consequently, the normally delicate, webbed walls of alveoli become stiff, disrupting the gaseous exchange between the alveolar epithelium and blood capillaries surrounding it, causing breathlessness and eventual death of the patient. However, the causes and progression of PF are less understood, and this has a strong bearing on designing effective therapies to fight this disease.

Evolution in the Treatment of Pulmonary Fibrosis

The modalities to treat PF have evolved significantly over the years and have thrown up some interesting facets. In the past, since PF was thought to be an outcome of lung inflammation, anti-inflammatory corticosteroids were unsuccessfully administered to affected individuals, worsening their health in some cases. Several standard therapies, which modulate the immune responses in our body, also fell out of favour due to their limited effectiveness and potential harm in the long run.

As the molecular nature of the fibrotic lungs was unravelled, two drugs called pirfenidone and nintedanib, which block certain biomolecules promoting fibrosis, were approved for treatment, and have become the mainstay to slow down the deterioration of affected lungs.^1,2 However, their impact on overall disease progression and long-term survival remains limited, highlighting the need for additional therapeutic approaches.

It may be noted here that approval of a drug or treatment strategy by a regulatory authority involves clinical trials conducted on human beings to study the safety and efficacy of the new treatment, and also examine if it is better than any of the existing approaches. They are divided into early (Phase I and II) and late (Phase III) trials.

In addition to medications, pulmonary rehabilitation programmes, which offer substantial benefits in improving lung function, have enhanced the quality of life in patients. But in severe cases of tissue damage, lung transplantation remains the only feasible option that improves the survival of patients, though this approach has its own set of health risks and is quite expensive.^1,4.

Novel Therapeutic Approaches Against Pulmonary Fibrosis on the Horizon

Decades of research on PF have identified several cellular targets and altered cell-cell communication pathways, which could be harnessed for future therapeutic interventions. One of the approaches is to target pathways involved in scarring of lungs to develop new therapeutic agents against fibrosis.

Recently, an anticancer drug called saracatinib has shown great promise in reducing scar formation in preclinical studies² (a stage of research that uses animal models or cell lines). Another approach is to repurpose existing anti-inflammatory and anti-cancer drugs, such as thalidomide, which has shown great promise in suppressing cough in patients with PF during early phase clinical trials.¹ Thus, advanced clinical trials are either underway or are being planned to ascertain the safety and effectiveness of these drugs.

Some studies have also revealed that cellular senescence (loss of cell's ability to divide and grow) contributes to the development of lung fibrosis. Hence, anti-cancer drugs like Dasatinib and Quercetin, which eliminate the senescent cells, have been shown to be greatly effective in improving the clinical symptoms in patients diagnosed with PF.⁵ Other strategies such as stem cell therapy, antibody therapy, and enzyme treatment are being explored as potential therapeutic measures^1,2 (please see Table no. 1 for details).

Several studies have shown that errors in the regulation of epigenetics can play an important role in the development of pulmonary fibrosis. In simple words, epigenetics is the study of how environment and behaviour can influence the activity of our genes. In preclinical studies, a group of epigenetic regulators known as histone deacetylase (HDACs), which showed impaired function in the lungs, were found to be inhibited by drugs such as suberoylanilide hydroxamic acid (SAHA) and valproic acid, offering newer therapeutic options.⁶

Finally, the identification of aberrant cell populations in fibrotic lungs, which contribute to defective mechanisms and pathological changes, presents a unique opportunity for targeted therapies by employing biomarkers. Considering the intricacies of PF, a combination therapy regimen, such as pirfenidone and nintedanib together, has proven to be more effective in many human populations around the globe.⁷ Hence, scientists are exploring if any other multi-pronged therapies could work better to completely reverse lung damage, at least in the early stages of PF.

Table No. 1: New therapeutic strategies or agents being developed against pulmonary fibrosis.

Due to the complexity of this disease, there is no “one-size-fits-all” treatment for PF and tailoring treatments for individual patients seems to help manage the disease better. Biomarkers, those which predict treatment responses, can help in developing personalized therapies to improve patient outcomes and facilitate the diagnosis, prognosis, and treatment of PF.

The Crusade to Find a Cure for Pulmonary Fibrosis

The battle against PF is far from over, as significant challenges have to be met in discovering strategies for its diagnosis, treatment, and overall management. Although a few therapies have provided some relief to patients, none of them offer a cure or ability to halt or reverse the disease in its tracks. The ongoing research in novel approaches, such as targeting molecular pathways and exploring alternative drugs, provides a glimmer of hope for the future.

However, the uncertainty encircling the molecular origin of this condition and the lack of differential diagnostic methods makes it one of the most challenging diseases to deal with in the field of pulmonary medicine. To accelerate progress, it is crucial to establish a global collaboration in research to enable quicker sharing of information on its detection, therapeutic methods, and biomarker discoveries in order to find a cure for PF.

The world’s brightest minds in the field of pulmonary medicine and research are taking significant steps in the fight against PF and breathing new life into diseased lungs. With every breakthrough, we are a step closer to winning the war against this dreaded lung disorder. Please bear in mind, hope is on the horizon, and even the most challenging of obstacles can be conquered.

Bibliography

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Authors: Swati Patidar and Satish Sasikumar*

Acknowledgments: The authors wish to thank Dr. Arvind Goja* and Dr. Lekshmi Sudha Devi for their helpful comments and suggestions.

*Genetics and Molecular Biology Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune, Maharashtra, PIN-411033, India. Author for correspondence: Dr. Satish Sasikumar (satish.sasikumar@dpu.edu.in); Ms. Swati Patidar (patidarrswati@gmail.com) is a student of the First Year Master in Biotechnology degree programme at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune.